N-methyl-D-aspartate receptor desensitisation is neuroprotective by inhibiting glutamate-induced apoptotic-like death.
Glutamate excitotoxicity is implicated in several neurodegenerative diseases; consequently, considerable effort has been made to elucidate neuroprotective mechanisms against such toxicity. N-Methyl-D-aspartate (NMDA) receptor desensitisation is one potential mechanism for controlling glutamate-mediated neuronal cell death. Pretreatment of rat cerebellar granule cells with subtoxic concentrations of NMDA caused a marked reduction in the calcium signals generated by subsequent glutamate stimulation, and, furthermore, this receptor desensitisation was coupled to a reduction in glutamate-induced apoptotic-like death. These effects were reduced by either D-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist, or cyclosporin A, an inhibitor of calcineurin. Thus, the results support a role for receptor desensitisation in protection from glutamate-mediated apoptotic-like neuronal cell death.
Wood
A M
AM
Division of Neuroscience, School of Biological Sciences, University of Manchester, England, UK.
Bristow
D R
DR
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000502:physiology; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure; D016572:Cyclosporine / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D007700:Kinetics; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*
D065095:Calcineurin Inhibitors; D002843:Chromatin; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D016572:Cyclosporine; D002118:Calcium